Invasive aspergillosis, a rapidly progressive, often-fatal fungal infection, can occur in patients undergoing allogeneic hematopoietic cell transplantation, and in other immunocompromised patients. Nurses are well-positioned to identify, educate, and monitor patients at high risk.

The patient, SR, is a 40-year-old woman who underwent matched unrelated donor bone marrow transplantation for Philadelphia chromosome–positive acute lymphocytic leukemia. The transplant was complicated by graft-versus-host disease (GVHD) requiring long-term immunosuppression. Thirteen months following transplant, SR presented with skin nodules and was found to have disseminated invasive aspergillosis (IA)infection involving the skin, lungs, and brain. The infection was successfully treated with voriconazole (Vfend).

Invasive aspergillosis is a rapidly progressive, often fatal infection that occurs in patients undergoing allogeneic hematopoietic cell transplantation (HCT) and in other immunocompromised patients.[1] Early diagnosis is critical to successful treatment, but diagnosis remains a challenge. Clinicians must be vigilant in assessing patients who are at risk, and therapy should be initiated promptly for probable or proven infections.

Aspergillus

Aspergillus is a ubiquitous fungus typically found in soil, dirt, dust, compost, or decaying matter. It produces large numbers of spores which are efficiently dispersed through the air and inhaled by humans. The spores are small and travel deep into the respiratory tract to the alveoli. In the alveoli, resident alveolar macrophages engulf the spores and release cytokines to recruit massive numbers of neutrophils, as part of the inflammatory response to eliminate the spores.[2] If the spores germinate in the respiratory tract, they produce hyphae that invade the surrounding tissue and which can disseminate to other organs via the bloodstream.[3]

In cases of invasive disease, neutrophils and other components of the innate immune system must work in collaboration with the adaptive immune system. The adaptive immune system comprises humoral immunity (B lymphocytes) and cellular immunity (T lymphocytes). T lymphocytes are known to play a major role in the eradication of Aspergillus; the role of B lymphocytes is less clear.[2] Because neutrophils and T lymphocytes are critical for preventing and eliminating Aspergillus, patients at risk for this opportunistic infection (see Table 1) include those with prolonged neutropenia or impaired cellular immunity, such as HCT recipients, patients with acute leukemia, and patients treated with medications that can cause prolonged impairment of T cell–mediated immunity (eg, monoclonal antibodies such as alemtuzumab [Campath] or infliximab [Remicade]; purine analogues; steroids).

Diagnosis

The most common site of infection is the lungs, owing to inhalation of spores, but infections can also occur in the sinuses or disseminate to the skin, central nervous system, or other organs. Invasive aspergillosis typically manifests with fever, cough, dyspnea, pleuritic chest pain, and/or hemoptysis, but symptoms often do not occur until late in the course of the infection.[4] The most common presentation is persistent fever in a patient with prolonged neutropenia or immunosuppression. Given that fever in an immunocompromised patient may have a variety of causes, diagnosis of IA remains a challenge, and clinicians must maintain a high degree of suspicion for the possibility of fungal infection in high-risk patients.

Diagnostic tests have historically been insensitive; Aspergillus is not generally found in routine blood cultures. Tissue specimens yield positive histology in 30%–50% of cases, and bronchoscopy only has 50% sensitivity.[5] High-resolution CT scans can be helpful to identify the characteristic radiologic findings: halo sign (an area of ground-glass infiltrate surrounding nodular densities), crescent sign (crescent of air surrounding nodules, indicative of cavitation), or cavitary lesions.[6] Newer tests that identify components of the Aspergillus cell wall components are available, such as 1) the Aspergillus galactomannan assay for plasma, serum, bronchoalveolar lavage fluid, or cerebrospinal fluid and 2) the β-D-glucan serum assay. Serum assays for Aspergillus continue to be studied with the goal of understanding how to optimize their use, but some experts recommend obtaining serial screening serum galactomannan assays in high-risk patients.[7] In the event of a positive galactomannan test, radiology studies should be obtained for further diagnostic evaluation.

According to current guidelines, treatment is initiated preemptively for high-risk patients who have radiologic signs and positive Aspergillus galactomannan and/or β-D-glucan assays.[8] The European Organisation for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group developed standardized diagnostic criteria for proven, probable, and possible invasive fungal disease, summarized in Table 2. Because of the challenge of early and accurate diagnosis, only 30% of patients treated for IA have proven disease, and approximately 70% of patients with IA at autopsy were never diagnosed clinically.[4] Since early diagnosis is critical to effective treatment of aspergillus infections, the overall outcome remains poor, with mortality rates of 30%–50%.[3] The chance of successful treatment is significantly lower for patients with persistent neutropenia and/or immunosuppression.[1]

Treatment Summary

The 40-year-old female patient, “SR," had undergone matched unrelated donor bone marrow transplantation for Philadelphia chromosome–positive acute lymphocytic leukemia. GVHD prophylaxis consisted of cyclosporine and methotrexate. Fluconazole at 400-mg PO daily was prescribed for antifungal prophylaxis. Two months following transplant, SR developed severe acute GVHD of the gastrointestinal tract. Cyclosporine was discontinued and she was treated initially with tacrolimus and solumedrol; later, mycophenolate mofetil (CellCept) was added to improve her response, and she received a treatment course with infliximab. The GVHD was very difficult to treat, and 1 year following transplant, SR continued to be TPN (total parenteral nutrition)-dependent and required triple immunosuppressive therapy with tacrolimus at 3 mg PO bid, mycophenolate mofetil at 1,500 mg PO bid, and prednisone at 20 mg PO qd. A regimen of liposomal amphotericin at 2.5 mg/kg every Monday, Wednesday, and Friday was employed for antifungal prophylaxis.

TABLE 1Patient-Related Risk Factors for Invasive Aspergillosis

During a routine clinic visit, SR was found to have a temperature of 38.1°C (about 101°F) and an elevated white blood cell count of 18.2 mm3 (normal range, 4–10 mm3). The nurse practitioner performed a physical examination which demonstrated several erythematous, tender, firm subcutaneous nodules, 1–5 mm in size, on SR’s right forearm, left chest, abdomen, and left leg. Dermatology consultation was obtained, and a skin biopsy/culture of two of the skin nodules revealed Aspergillus. Diagnostic workup included CT scans of the chest, abdomen, and pelvis, which demonstrated a 2.8-cm perihilar mass, and an MRI of the brain, which demonstrated two small enhancing right frontal lobe lesions. Blood cultures were negative.

SR was diagnosed with disseminated Aspergillus infection involving the skin, lungs, and brain. Treatment with voriconazole was initiated at a loading dose of 6 mg/kg IV bid. This was followed by a maintenance dose of 4 mg/kg IV bid, followed by voriconazole at 200 mg PO bid.

Nursing Management

Prior to administering voriconazole, the nurse reviewed SR’s renal and hepatic function blood tests. Voriconazole is administered intravenously with a loading dose of 6 mg/kg every 12 hours for the first 24 hours, then a maintenance dose of 4 mg/kg every 12 hours for a minimum of 7 days. Therapy may then be switched to the oral formulation at a dose of 200 mg Q12h. The intravenous formulation of voriconazole is prepared in a cyclodextrin solution that is excreted through the kidneys, and dose adjustment is necessary for patients with renal dysfunction. No dose adjustment is necessary for oral voriconazole. Voriconazole is metabolized hepatically and can cause hepatotoxicity, so liver function tests should be evaluated at baseline and during the course of therapy.[1] Patients who develop abnormal liver function tests should be monitored for the development of more severe hepatic injury. Elevated serum bilirubin, alkaline phosphatase, and hepatic aminotransferase enzyme levels may be seen and may require discontinuation of the drug.

TABLE 3Drug Interactions With Voriconazole

The nurse and the pharmacist reviewed SR’s current medications to determine potential drug interactions. Because voriconazole inhibits the activity of cytochrome P450 isoenzymes CYP2C19, CYP2C9, and CYP3-A4, there is potential for voriconazole to interact with other medications metabolized by those enzymes. The following drugs decrease the concentration of voriconazole, and their concomitant use is contraindicated: rifampin, rifabutin, ritonavir (Norvir), St. John’s Wort, carbamazepine, and long-acting barbiturates. Voriconazole increases the concentration of astemizole, pimozide (Orap), quinidine, sirolimus (rapamycin, Rapamune), and ergot alkaloids, and their concomitant use is contraindicated. Voriconazole also increases the concentration of other medications, such as alfentanil (Alfenta), fentanyl, oxycodone, cyclosporine, methadone, tacrolimus, warfarin, statins, benzodiazepines, calcium-channel blockers, sulfonylureas, vinca alkaloids, and nonsteroidal anti-inflammatory drugs (NSAIDs), therefore their coadminstration with voriconazole requires careful monitoring and potential dose modification. Other drugs that require frequent monitoring and/or dose adjustment when administered with voriconazole include efavirenz (Sustiva), phenytoin, omeprazole, and oral contraceptives. Table 3 lists monitoring and dose modifications that are recommended for selected medications when used concomitantly with voriconazole. SR required tacrolimus for continued treatment of GVHD, so the nurse obtained tacrolimus levels three times weekly and the nurse practitioner adjusted the tacrolimus dose to maintain it within the therapeutic range.

The nurse educated SR about taking the voriconazole pills 1 hour before or after meals, twice a day. The presence of high-fat food affects voriconazole absorption; when taken on an empty stomach, its bioavailability is 96%.[7] The nurse cautioned SR that voriconazole might cause transient visual disturbances such as altered⁄enhanced visual perception, blurred vision, color vision change, or photophobia. In clinical trials, approximately 30%–40% of subjects experienced mild temporary visual disturbances that usually occurred about half an hour after administration of voriconazole, generally spontaneously resolved within an hour, and occurred most often during the first week of treatment.[7,9] The visual reactions are generally mild and transient. They are thought to be completely reversible, with no long-term effects, and seldom require discontinuation of therapy.[7] The nurse advised SR to avoid driving both at night and if she was experiencing visual disturbances.

The nurse educated SR to avoid strong, direct sunlight and wear sunscreen, to reduce her risk of photosensitivity skin reactions and rashes in sunlight-exposed areas that may occur with voriconazole.[1] In patients who have undergone allogeneic HCT (hematopoietic cell transplantation), it is particularly important to remember this potential side effect, since a rash may be mistaken for GVHD of the skin.[10]

Voriconazole metabolism is variable, and measurement of trough voriconazole levels correlates with effectiveness and toxicity. Research suggests that voriconazole levels in the range of 2–6 mg/L may be associated with the optimal response, and levels > 6 mg/L are associated with increased hepatotoxicity.[11] Future studies are needed to confirm these data so that guidelines can be developed for therapeutic drug monitoring.

Although Aspergillus is universally present in the environment, nurses can educate patients about how to minimize their risk by avoiding situations and activities in which inhalation of aerosolized spores is more likely. High airborne spore counts occur in the environment near organic debris; therefore, high-risk patients should avoid gardening, dusting, vacuuming, composting, construction sites, and leaf blowers. In the hospital setting, the Centers for Disease Control and Prevention (CDC) recommends high-efficiency particulate air (HEPA) filtration and protective isolation for high-risk patients, to prevent aspergillosis.[12] The CDC also recommends that patients wear N95 respirators when they leave their hospital rooms. Although there is no evidence to support the use of N95 masks to prevent aspergillosis, clinicians commonly recommend their use to high-risk patients. A recent randomized controlled trial studied the effectiveness of N95 masks to prevent IA and demonstrated that there was no benefit to their use.[13] A larger study is warranted to confirm these findings.

Discussion

This case underscores the importance of thoroughly investigating new symptoms in an immunocompromised patient. Cutaneous aspergillosis usually results from hematogenous dissemination after primary infection originating in the lungs. In severely immunocompromised patients, a low-grade fever and leukocytosis are nonspecific signs with a wide differential. The skin nodules represented a visible manifestation of disseminated infection, and prompted a diagnostic evaluation resulting in identification of the aspergillosis and initiation of therapy.

FDA-approved treatment options for IA include amphotericin B and its lipid formulations, voriconazole, itraconazole (Sporanox), posaconazole (Noxafil), and caspofungin (Cancidas).[1] Of these agents, voriconazole and amphotericin B are indicated for the initial treatment of IA. Liposomal amphotericin B products, itraconazole, and caspofungin are indicated for salvage therapy. Posaconazole is FDA-approved for prophylaxis of IA in neutropenic patients with leukemia and myelodysplasia, and in allogeneic HSCT recipients with GVHD. Micafungin (Mycamine) and anidulafungin (Eraxis) are newer agents that also have activity against IA, but they have not been FDA-approved for IA pending further research.

Amphotericin B was once the gold standard for treatment of invasive fungal infection, although its use was limited by toxicities including nephrotoxicity, infusion reactions, electrolyte disturbances, and anemia. Voriconazole was FDA-approved in 2003 and is currently the initial treatment choice for IA, based on a clinical trial that demonstrated superior effectiveness and a tolerable side-effect profile, compared with amphotericin B.[1,9] Voriconazole is a broad-spectrum triazole that is active in vitro against various yeasts and molds, including Aspergillus species. It can be given orally and intravenously. In the pivotal trial comparing voriconazole against amphotericin B for primary treatment of invasive aspergillosis, the median overall survival rate was 71% for patients treated with voriconazole, compared with 58% for those treated with amphotericin B, and there was significantly less toxicity associated with voriconazole.[9]

Treatment of invasive pulmonary aspergillosis should be continued throughout the period of immunosuppression and until lesions have resolved; the minimum duration of therapy is 6–12 weeks.[1]

Outcome

One month after initiation of voriconazole, follow-up CT scan of SR’s chest showed a decrease in the size of the right perihilar pulmonary lesion, to 1.2 cm. Two months after initiation of voriconazole, a repeat CT scan of her chest and an MRI of her brain demonstrated complete resolution of the lesions, and clinical examination demonstrated complete resolution of her skin nodules. SR did not experience any visual disturbances from voriconazole, but after 3 months of therapy, she developed a transient mild transaminitis which resolved with discontinuation of the drug. She continued to require immunosuppression to control the GVHD, so after her hepatic function normalized she was rechallenged with voriconazole and experienced no further side effects.

Conclusion

Invasive aspergillosis is a major life-threatening infection in immunocompromised patients. Infection risk depends upon the immune status of the individual, and preventive strategies are limited. Nurses are well positioned to identify patients at high risk of IA and monitor them for symptoms. Improved diagnostic tests and the availability of more effective antifungal treatments are contributing to improved survival following IA infection.

Financial Disclosure:The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

6. De Pauw B, Walsh TJ, Donnelly JP, et al: Revised definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group. Clin Infect Dis 46(12):1813–1821, 2008.

7. Ruping MJ, Vehreschild JJ, Cornely OA: Patients at high risk of invasive fungal infections: When and how to treat. Drugs 68(14):1941–1962, 2008.